Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis.

In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m/day,1 mg/m/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained.

Clinical trials in pediatric ALS: a TRICALS feasibility study.

Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.

Evoked and Event-Related Potentials as Biomarkers of Consciousness State and Recovery.

The definition of consciousness has been the subject of great interest for many scientists and philosophers. To better understand how evoked potentials may be identified as biomarkers of consciousness and recovery, the different theoretical models sustaining neural correlates of consciousness are reviewed. A multimodal approach can help to better predict clinical outcome in patients presenting with disorders of consciousness.

BAG3 and BAG6 differentially affect the dynamics of stress granules by targeting distinct subsets of defective polypeptides released from ribosomes.

Stress granules (SGs) are dynamic ribonucleoprotein granules induced by environmental stresses. They play an important role in the stress response by integrating mRNA stability, translation, and signaling pathways. Recent work has connected SG dysfunction to neurodegenerative diseases.

Tetrodotoxin-Sensitive Neuronal-Type Na Channels: A Novel and Druggable Target for Prevention of Atrial Fibrillation.

Background Atrial fibrillation (AF) is a comorbidity associated with heart failure and catecholaminergic polymorphic ventricular tachycardia. Despite the Ca-dependent nature of both of these pathologies, AF often responds to Na channel blockers. We investigated how targeting interdependent Na/Ca dysregulation might prevent focal activity and control AF.

G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial).

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN.

Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water: A long-term follow-up.

Some studies have reported an association between overexposure to selenium and risk of amyotrophic lateral sclerosis (ALS), a rare degenerative disease of motor neurons. From 1986 through 2015, we followed a cohort in Northern Italy that had been inadvertently consuming tap water with unusually high concentrations of inorganic hexavalent selenium from 1974 to 1985. We had previously documented an excess incidence of ALS in this cohort during 1986-1994.

Serial ultrasound assessment of diaphragmatic function and clinical outcome in patients with amyotrophic lateral sclerosis.

Background: Diaphragmatic assessment by ultrasound (US) is a non-invasive and useful method in the clinical management of patients with Amyotrophic Lateral Sclerosis (ALS). The aim of our observational study was to evaluate the impact of serial assessment of the diaphragmatic function by US on long-term outcomes in a series of patients suffering from ALS and to correlate US indices of diaphragmatic function and respiratory function tests with these outcomes.

Methods: A cohort of 39 consecutive patients has been followed up to 24 months.

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

To assess masitinib in the treatment of ALS. Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.

ALS and FTD: Where RNA metabolism meets protein quality control.

Recent genetic and biochemical evidence has improved our understanding of the pathomechanisms that lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with overlapping symptoms and causes. Impaired RNA metabolism, enhanced aggregation of protein-RNA complexes, aberrant formation of ribonucleoprotein (RNP) granules and dysfunctional protein clearance via autophagy are emerging as crucial events in ALS/FTD pathogenesis. Importantly, these processes interact at the molecular level, converging on a common pathogenic cascade.

Rivaroxaban in cervical and "cervico-cerebral" artery dissections: a new therapeutic option?

Antiplatelet agents and vitamin K antagonists (VKA) are usually used in the treatment of cervical (carotid or vertebral) artery dissections (CADs); however, data about the use of direct oral anticoagulants (DOACs) in these conditions are very limited. DOACs have proven to be effective in stroke reduction in non-valvular atrial fibrillation and, when possible, they are preferred to warfarin because of their better safety profile. We describe four cases of CADs and, firstly in literature, cervico-cerebral (CCADs) in young patients (average age of 42 years) treated with rivaroxaban 20 mg daily.

Psychiatric Symptoms in Amyotrophic Lateral Sclerosis: Beyond a Motor Neuron Disorder.

The historical view that Amyotrophic Lateral Sclerosis (ALS) as a pure motor disorder has been increasingly challenged by the discovery of cognitive and behavioral changes in the spectrum of Frontotemporal Dementia (FTD). Less recognized and still significant comorbidities that ALS patients may present are prior or concomitant psychiatric illness, such as psychosis and schizophrenia, or mood disorders. These non-motor symptoms disturbances have a close time relationship with disease onset, may constitute part of a larger framework of network disruption in motor neuron disorders, and may impact ALS patients and families, with regards to ethical choices and end-of-life decisions.

Post-infectious sensory neuropathy with anti-GT1a and GQ1b antibodies associated with cold urticaria.

A 64 years-old woman presented subacute onset distal paraesthesia concurrently with cold-induced urticaria, a rare form of physical urticaria. Both the disturbances developed a fortnight after an upper respiratory tract infection. EMG confirmed an exclusively sensory polyneuropathy, with prolongation of distal latencies and reduction of amplitudes.

Medication-overuse headache: a widely recognized entity amidst ongoing debate.

Medication overuse in primary headache disorders is a worldwide phenomenon and has a role in the chronification of headache disorders. The burden of disease on individuals and societies is significant due to high costs and comorbidities. In the Third Edition of the International Classification of Headache Disorders, medication-overuse headache is recognized as a separate secondary entity next to mostly primary headache disorders, although many clinicians see the disease as a sole complication of primary headache disorders.

Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial).

Introduction: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.

Riluzole and other prognostic factors in ALS: a population-based registry study in Italy.

Objective: In this prospective population-based registry study on ALS survival, we investigated the role of riluzole treatment, together with other clinical factors, on the prognosis in incident ALS cases in Emilia Romagna Region (ERR), Italy.

Methods: A registry for ALS has been collecting all incident cases in ERR since 2009. Detailed clinical data from all patients diagnosed with ALS between 1.

Redox speciation of iron, manganese, and copper in cerebrospinal fluid by strong cation exchange chromatography - sector field inductively coupled plasma mass spectrometry.

A new method of simultaneous redox speciation of iron (II/III), manganese (II/III), and copper (I/II) in cerebrospinal fluid (CSF) has been designed. For the separation of redox species strong cation exchange chromatography (SCX) with isocratic elution was employed. Species were detected using inductively coupled plasma sector field mass spectrometry (ICP-sf-MS), operating at medium resolution.

Elevated Levels of Selenium Species in Cerebrospinal Fluid of Amyotrophic Lateral Sclerosis Patients with Disease-Associated Gene Mutations.

Background: Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons.

Objective: Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls.

Amyotrophic lateral sclerosis and myasthenia gravis: association or chance occurrence?

Very few cases of patients with myasthenia gravis (MG) who later developed amyotrophic lateral sclerosis (ALS) have been described, although some studies showed that significantly more cases than expected have ALS associated with a prior diagnosis of autoimmune diseases. Our aim was to investigate whether the association of ALS and MG was higher than expected in a population-based study and to describe the clinical features characterizing these patients. In Emilia Romagna Region of Italy, a prospective registry has been collecting all incident ALS cases since 1.